The present invention relates to delivery systems that allow for sustained release of one or more solutes. In particular, the present invention relates to devices for delivering substances to the body of an animal or into other environments requiring a constant delivery and to methods of delivering these substances in a constant, sustained-release fashion.
Drug delivery classically has been via oral dosage forms that release the drug as they dissolve in the gastrointestinal tract. These delivery systems typically provide for rapid release of the active substance, which leads to the presence of maximal concentrations of the drug in the blood followed by a rapid decrease in concentration as the drug is metabolized and cleared. At these maximal concentrations, many drugs are highly toxic. Furthermore, if the concentration decreases rapidly in the body, then the time during which there is a therapeutically-effective level is short, and therapeutic efficacy requires administration of multiple doses. In addition, if release of a substance in the body cannot be controlled, then it may not be effectively delivered to the site of the body requiring treatment.
Other solutes also benefit from devices that allow for their sustained release. For example, dosing of swimming pools with chlorine or hot tubs with bromine as anti-microbial agents currently requires adding these substances to the water on a fairly regular basis. Furthermore, if the concentration is not controlled and becomes too high upon addition, then the water may not be safe or pleasant for bathers until the concentration stabilizes at lower values. Other uses for sustained-release delivery systems include, for example, delivery of food or insecticides to plants, delivery of vaccines, antibiotics, anti-parasitic agents, growth promotants or other drugs to livestock, delivery of sanitizing agents or perfumes to toilets or septic tanks, delivery antibiotics or other drugs to companion animals, delivery of dyes, bleaches or other substances in the processing of textiles, delivery of algicides to water towers or ponds, delivery of food to fish in aquaria or ponds, and delivery of any substance requiring constant delivery in an industrial manufacturing process.
Various sustained release delivery devices have been described, including those in which a solute is contained within an impermeable housing with one or more openings from which solute egresses by diffusion. Such devices purport to deliver solute at a constant (zero-order) rate; however, many deviate significantly from zero order or linear delivery. In addition, such devices often are limited in the amount of total dose deliverable, as well as by fixed parameters that make it difficult or impossible to adjust the delivery kinetics. A common feature of such prior art devices is that their release kinetics are characterized by an initial burst of solute release prior to a period of relatively constant rate of release, and the relatively constant rate of release often only crudely approximates zero order. For several reasons, such an initial burst is undesirable, as it temporarily delivers a dose in excess of the desired, effective dose, thus wasting solute, and moreover, may deliver an amount of solute which is toxic or otherwise damaging in the particular application. In addition, the initial release of a large amount of solute reduces the total amount of solute subsequently available for prolonged release by the device, thus shortening the duration of relative constant delivery, reducing its effective life and requiring more frequent replacement.
The devices and methods of the present invention overcome the disadvantages of current devices and methods for the delivery of solutes by providing for reliable and adjustable sustained release of solutes in aqueous and non-aqueous environments. In addition to exhibiting adjustable, nearly-constant release rates over suitably prolonged periods of time, the devices and methods of the invention provide for modulation or suppression of the aforementioned initial burst. The devices and methods of the invention may be applied to any of the prior-art devices relying on a fenestration or orifice and a fluid- and solute-impervious coating, to provide prolonged and near zero-order release.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.
In a first embodiment, the present invention relates to a device for the continuous, linear, sustained release of one or more solutes. The device comprises at least one dispenser, each dispenser comprising at least one solute reservoir element, the solute reservoir element defined by a fluid-impervious and solute-impervious wall and having at least one orifice therein referred to as a source element, each source element being in fluid registry with a gradient-forming element, the gradient-forming element having a release orifice. The gradient-forming element is provided for preventing unwanted initial burst and release of solute while promoting controlled, prolonged near-zero-order release.
The solute reservoir element may have a shape such as but not limited to a hemisphere, sphere, pyramid, cylinder, tetrahedron, parallelepiped, or polyhedron. A hemisphere- or pyramid-shaped solute reservoir element is preferred. A hemispherical solute reservoir element is most preferred. Preferably, the ratio of the radius of a hemisphere or portion thereof representing the maximum internal diffusion surface of the solute reservoir element, to the radius of the source element, is equal to or greater than about two, and more preferably, the ratio is greater than or equal to about five. Most preferably, the ratio is equal to or greater than about ten.
The source element is an opening or passageway between the solute reservoir element and the gradient-forming element. It preferably has a circular cross-section but is not so limiting, and may have any shape.
The gradient-forming element may have a shape such as but not limited to a hemisphere, sphere, pyramid, cylinder, tetrahedron, parallelepiped, or polyhedron. Preferably, the gradient-modifying element is a pyramid, the most preferable pyramid a truncated right circular cone (a frustum). More preferred is a right circular cone with a vertex angle of between about 10xc2x0 and about 135xc2x0, and even more preferred is a vertex angle of about 60xc2x0 to about 120xc2x0. Preferably, the relationship among the dimension of the gradient-forming element extending from the source element to the release orifice (referred to herein as the height of the gradient-forming element) and the radii of the release orifice and the source element are such that the height of the gradient-forming element is less than about four times the ratio of the square of the radius of the source element to the radius of the release orifice. More preferably, the height of the gradient-forming element is less than about two times the aforementioned ratio, and most preferably, the height of the gradient-forming element is less than two times the aforesaid ratio but greater than one-tenth the aforementioned ratio.
In another preferred embodiment of the present invention, the foregoing device has a cylindrical gradient-forming element, one end of the cylinder in fluid registry with the source element, and the other end providing the release orifice. Preferably, the ratio of the radius of the hemisphere comprising the solute reservoir element to the radius of the source element is equal to or greater than about two, more preferably equal to or greater than five, and most preferably equal to or greater than ten. The height of the cylinder is preferably less than about four times its radius, more preferably less than about two times its radius, and most preferably 0.1 to 2 times its radius. Such devices are particularly useful for oral delivery of a therapeutic agent, although it is not so limiting.
In another embodiment, the device of the present invention may have a solute reservoir element in the shape of a truncated spherical cone or a truncated right circular cone. The gradient-forming element may have a shape among those described above; preferred is a cylindrical shape. Preferably, the radius of a hemisphere or portion thereof contained within the cone and representing the maximum internal diffusion surface is greater than twice the radius of the source element; more preferred is a hemisphere having a radius five to ten times the radius of the source element; most preferred is a hemisphere having a radius more than ten times the radius of the source element. The length of the gradient-forming element extending from the opening preferably is less than four times its radius, more preferably less than two times its radius, and most preferably, 0.1 to 2 times its radius. The gradient-forming element may also have a shape of a truncated right circular cone, wherein the base of the gradient-forming element is in fluid registry with the opening of the cone-shaped solute reservoir element, the dispenser thus having the appearance of a smaller cone extending from the vertex of the larger.
In yet another embodiment of the invention, modifications of dispenser with the foregoing characteristics but having the same or similar properties are embraced herein. For example, a dispenser particularly suitable for parenteral use, such as providing at a subcutaneous location, takes the form of a cylindrical-shaped solute reservoir element. A longitudinal sector of the cylinder is absent, the walls of the cylinder fluid- and solute-impervious. The absent longitudinal sector-shaped cavity in the cylinder forms the aforementioned gradient-forming element, and its interface exterior to the cylinder""s overall shape forms the release orifice. The source element providing solute from the solute reservoir element to the gradient-forming element is provided in the form of a series of openings in at least one or both of the two flat faces forming the sector. A series of rows of openings parallel to the longitudinal axis of the cylinder are provided, with the rows more closely spaced to the interior of the sector (i.e., towards the center), and becoming less closely spaced approaching the exterior surface of the cylinder.
A similar configuration may also be provided by variously-shaped solute reservoir elements which are provided with a deep indentation, invagination or cavity contiguous with the exterior of the dispenser, the indentation forming the gradient-forming element. The solute reservoir element and the indentation are fluid- and solute-impervious. As in the previous embodiment, a series of openings between the solute reservoir element and the gradient-forming element provide the necessary source elements. If a series of rows of openings are provided, they may be more closely spaced distal to the interface between the gradient-forming element and the exterior of the dispenser, and become less-closely spaced towards the exterior. A solute reservoir element of the invention may have multiple cavity-type gradient-forming elements, of a combination of both cavity-type gradient-forming elements and the type of exterior gradient-forming element described above, such as a cone or cylindrical extension from the solute reservoir element. Thus, the invention embodies both interior and exterior gradient-forming elements, or combinations thereof in a single dispenser or device. Such devices provide the desired release characteristics as described herein, with a zero-order or near zero-order type kinetics and absence of an initial burst. As noted with the other dispensers, the geometry and dimensions of the devices with interior gradient-forming elements may be easily tailored to the particular application or needs of the device, including the location, duration, flux, permanence, biodegradability, among other factors.
Any discussion herein of the general features or aspects of the devices of the invention are applicable to any or all of the foregoing embodiments.
In one aspect the solute reservoir element of a device of the invention is empty. In another embodiment, the solute reservoir element contains a porous substrate. In yet another embodiment, the solute reservoir element contains one or more solutes, with or without a porous substrate. The release orifice may be coated with a material that is soluble under preselected conditions, such as a preselected pH.
The one or more solutes contained within a device of the invention may be, by way of non-limiting example, is a therapeutic agent. Examples of such therapeutic agents include a calcium salt, parathyroid hormone, antihypertensive agents, diuretics, sympatholytic drugs, vasodilators, calcium channel blockers, analgesics, opioids, non-steroidal anti-inflammatory agents, antihistamines, antidepressants, hypnotics, sedatives, antiepileptic agents, antiarrhythmic agents, antiparasitic agents, antimicrobial agents, chloroquine, anti-Parkinson agents, antineoplastic agents, contraceptives, hypoglycemics, electrolytes, vitamins, minerals, nutriceuticals, local anesthetics, diagnostic agents, peptide growth factors, hormones, cytokines, stimulants, amphetamine, methylphenidate, antianxiety agents, benzodiazepines, hematopoietic agents, erythropoietin, stem cell factor, interleukins, and mixtures thereof. In a preferred embodiment, the one or more solutes is an erythropoietin or a chloroquine.
The one or more solutes may be dissolved in a solvent or pharmaceutically acceptable vehicle, or it may be present in the device in a dry form. In one embodiment, the one or more solutes is not water soluble. A device of the invention may also include a solute-modifying agent.
In another broad aspect, the invention is directed to a method for delivering one or more solutes in a linear, sustained release fashion, by administering to a desired site of delivery at least one devices as mentioned above. Such delivery may be orally, sub-lingually, rectally, vaginally, sub-dermally, intramuscularly, ocularly, topically, nasally, aurically, intravenously, or directly into a particular anatomical location.
In a further broad aspect, the invention is directed to a kit comprising at least one device as mentioned above.
Variations in the design of the dispensers of the invention which provide the desired release properties are fully embraced herein. For example, a dispenser may have a single source element, a single gradient-forming element, and a single release orifice. Another variation comprises a plurality of release orifices. In another embodiment, a dispenser may have a plurality of source elements, each source element with its own gradient-forming element. In yet another embodiment, a gradient-forming element may be associated with several source elements, and in a further embodiment, a solute reservoir may have a plurality of such gradient-forming elements, each with multiple source elements. Moreover, a dispenser may have multiple gradient-forming elements, each of which provide a preselected but different release kinetics attributable to the entire dispenser.
The dispenser may have a shape selected from the group consisting of cone, cylinder, sphere, ellipse, hemisphere, capsule, rod, needle, and sheet. The dispenser or release orifice thereof may be covered or coated with a removable material to prevent release of the solute until the housing had resided in a particular location for a predetermined time period, or is subject to particular conditions which cause the material to become dislodged and initiate release.
The device of the invention may be adapted to hold one or more of the aforedescribed dispensers. By way of non-limiting examples, the device may be singly or multiply fenestrated to permit egress of solute to the environment after egress from the at least one dispenser contained therein, or the device may be designed to open or degrade to release the individual dispensers after a certain time period or under certain conditions. In a further example, the device may be provided with at least one exterior opening in fluid registry with a release orifice in a dispenser contained within. For a device with a plurality of such exterior openings, each orifice associated with a release orifice of a dispenser, each exterior opening is at least three release-orifice-radii apart from another, preferably ten radii apart.
The solute reservoir element may be filled with one or more solutes in adequate quantity to supply the source element of the device, and the gradient-forming element optionally may be filled with the one or more solutes.
In a second broad aspect, the present invention relates to a method for delivering one or more solutes in a linear, sustained release fashion, comprising administering to the site of delivery said solute or solutes in a device comprising at least one dispenser as described hereinabove, the dispenser containing at least one solute or capable of being filled with at least one solute. Using the device, the one or more solutes may be delivered into the body of an animal, for example, orally, sub-lingually, rectally, vaginally, sub-dermally, intramuscularly, ocularly, nasally, aurically, intravenously, on the surface of the skin, or directly into a specific anatomical location.
In a third aspect, the present invention relates to a kit, comprising a device for the continuous, linear, sustained release of a solute, the device comprising at least one dispenser as described hereinabove.
These and other aspects of the present invention will be better appreciated by reference to the following drawings and Detailed Description.